Sentinel node mapping for gastric cancer: a prospective multicenter trial in Japan.

PURPOSE: Complicated gastric lymphatic drainage potentially undermines the utility of sentinel node (SN) biopsy in patients with gastric cancer. Encouraged by several favorable single-institution reports, we conducted a multicenter, single-arm, phase II study of SN mapping that used a standardized dual tracer endoscopic injection technique. PATIENTS AND METHODS: Patients with previously untreated cT1 or cT2 gastric adenocarcinomas < 4 cm in gross diameter were eligible for inclusion in this study. SN mapping was performed by using a standardized dual tracer endoscopic injection technique. Following biopsy of the identified SNs, mandatory comprehensive D2 or modified D2 gastrectomy was performed according to current Japanese Gastric Cancer Association guidelines. RESULTS: Among 433 patients who gave preoperative consent, 397 were deemed eligible on the basis of surgical findings. SN biopsy was performed in all patients, and the SN detection rate was 97.5% (387 of 397). Of 57 patients with lymph node metastasis by conventional hematoxylin and eosin staining, 93% (53 of 57) had positive SNs, and the accuracy of nodal evaluation for metastasis was 99% (383 of 387). Only four false-negative SN biopsies were observed, and pathologic analysis revealed that three of those biopsies were pT2 or tumors > 4 cm. We observed no serious adverse effects related to endoscopic tracer injection or the SN mapping procedure. CONCLUSION: The endoscopic dual tracer method for SN biopsy was confirmed as safe and effective when applied to the superficial, relatively small gastric adenocarcinomas included in this study.

Spontaneous clearance of Helicobacter pylori after pylorus-preserving gastrectomy for gastric cancer.

Residual mucosa in the gastric stump after pylorus-preserving gastrectomy (PPG) is considered a risk factor for the development of gastric stump carcinoma (GSC). Duodenogastric reflux (DGR) and Helicobacter pylori (H. pylori) infection are suspected to contribute to the development of GSC. The aim of this study was to investigate the prevalence of H. pylori in the residual stomach after PPG for gastric cancer and to assess factors associated with the presence of H. pylori. We investigated 72 patients who had undergone PPG at least 1 year prior to the study and were confirmed to be positive for H. pylori infection on presurgical endoscopic biopsy. The extent of DGR, the prevalence of H. pylori infection based on H. pylori stool antigen (HpSA) tests and the severity of gastritis were analyzed in these post-PPG patients. None of the patients had DGR, as shown by (99m)Tc-PMT. Of the 72 post-PPG patients, 33 (46%) were positive for HpSA. The prevalence of H. pylori infection was significantly lower after surgery than before surgery. The endoscopic severity of remnant gastritis, as well as histological inflammation and activity, were higher in H. pylori-positive patients than in H. pylori-negative patients. In conclusion, some patients who undergo PPG and are negative for DGR experience spontaneous clearance of H. pylori infection.

Impact of inflammation-metaplasia-adenocarcinoma sequence and prevention in surgical rat models.

The incidence of esophageal cancer continues to rise in the Western world. Prior studies have suggested that gastroduodenal content reflux from gastroesophageal reflux disease induces the inflammation-mediated progression from hyperplasia to metaplasia, and to adenocarcinoma. We further investigated the sequential development of esophageal adenocarcinoma (EADC) with the use of an established surgical rat model. The present paper will describe the impact of the inflammation-metaplasia-adenocarcinoma sequence and chemoprevention in surgical rat models. A clinically relevant rat reflux model was used to investigate the cause of carcinogenesis, the sequential development of adenocarcinoma and chemoprevention with the use of a proton pump inhibitor. We found that duodenal reflux plays an important role in the inflammation-induced transformation of esophageal mucosa to adenocarcinoma. We were able to inhibit this transformation with rabeprazole, a proton pump inhibitor. Duodenal reflux promotes inflammation in the esophagus. The inflammation-metaplasia-adenocarcinoma sequence is important in the progression and development of EADC. Carcinogenesis can be prevented with chemoprevention agents such as rabeprazole. These results will need to be validated in clinical trials.

The severity of duodeno-esophageal reflux influences the development of different histological types of esophageal cancer in a rat model.

The mechanism through which each histological type of carcinoma arises from the esophageal mucosa remains unknown. This study was designed to investigate whether there is an association between the severity of duodeno-esophageal reflux and the histological type of esophageal cancer. A series of 120 male Fischer rats, weighing ∼180 g, were randomized to receive one of the following procedures: duodeno-forestomach reflux (DFR) with reduced exposure to duodenal contents, duodeno-esophageal reflux (DER) with increased exposure to duodenal contents and three control operations (DFR, DER control and sham). The reflux of bile was estimated with (99m)Tc-PMT scintigraphy. All animals were fed a standard diet without carcinogen. The esophageal mucosa was assessed 50 weeks after surgery for carcinoma. The median scanned fraction rate of duodeno-esophageal reflux was significantly lower for the rodents in the DFR group than those in the DER group. Five of 28 rodents in the DFR group and 17 of the 22 rodents in the DER group developed esophageal carcinoma. None of the controls developed carcinoma. The five rodents in the DFR group developed SCC. Of 22 esophageal carcinomas for the DER group, nine were SCC, 12 ADC and one was adenosquamous carcinoma. The fraction of esophageal SCC for the DFR group was significantly higher than that for the DER group, while the fraction of esophageal ADC for the DFR group was significantly lower than that for the DER group. These observations suggest that the severity of duodeno-esophageal reflux in rodents is related to the development of different histological types of esophageal carcinoma.

Barrett's esophagus and animal models.

The following on Barrett's esophagus (BE) and animal models contains commentaries on the factors of BE carcinogenesis; a duodenoesophageal reflux model; translation of targeted therapies for esophageal adenocarcinoma; and novel target regimens selected through a proteomics screen.

Inflammation-related carcinogenesis and prevention in esophageal adenocarcinoma using rat duodenoesophageal reflux models.

Development from chronic inflammation to Barrett's adenocarcinoma is known as one of the inflammation-related carcinogenesis routes. Gastroesophageal reflux disease induces regurgitant esophagitis, and esophageal mucosa is usually regenerated by squamous epithelium, but sometimes and somewhere replaced with metaplastic columnar epithelium. Specialized columnar epithelium, so-called Barrett's epithelium (BE), is a risk factor for dysplasia and adenocarcinoma in esophagus. Several experiments using rodent model inducing duodenogastroesophageal reflux or duodenoesophageal reflux revealed that columnar epithelium, first emerging at the proliferative zone, progresses to dysplasia and finally adenocarcinoma, and exogenous carcinogen is not necessary for cancer development. It is demonstrated that duodenal juice rather than gastric juice is essential to develop esophageal adenocarcinoma in not only rodent experiments, but also clinical studies. Antireflux surgery and chemoprevention by proton pump inhibitors, nonsteroidal anti-inflammatory drugs, selective cyclooxygenase-2 inhibitors, green tea, retinoic acid and thioproline showed preventive effects on the development of Barrett's adenocarcinoma in rodent models, but it remains controversial whether antireflux surgery could regress BE and prevent esophageal cancer in clinical observation. The Chemoprevention for Barrett's Esophagus Trial (CBET), a phase IIb, multicenter, randomized, double-masked study using celecoxib in patients with Barrett's dysplasia failed to prove to prevent progression of dysplasia to cancer. The AspECT (Aspirin Esomeprazole Chemoprevention Trial), a large multicenter phase III randomized trial to evaluate the effects of esomeprazole and/or aspirin on the rate of progression to high-grade dysplasia or adenocarcinoma in patients with BE is now ongoing.

Transectional gastrectomy: an old but renewed concept for early gastric cancer.

Segmental resection of the stomach was first described at the end of the 19th century by Mikulicz, who devised it to preserve the pylorus when performing gastric ulcer surgery. Although this technique was abandoned because of delayed gastric emptying, in 1967 Maki et al. developed a new improved concept of segmental gastrectomy: pylorus-preserving gastrectomy (PPG). The dramatic decrease in the occurrence of gastric ulcers limited the opportunity to perform these operations; however, PPG was then used for treating early gastric cancer, the incidence of which has increased remarkably over the last two decades. From the viewpoint of surgical oncology, a rationale to justify reducing the range of lymphadenectomy is required for preserving the curability. Therefore, we devised a new technique of transectional gastrectomy using sentinel node navigation for early gastric cancer located in the middle third of the stomach. The results of a questionnaire about postoperative symptoms and endoscopic assessment indicated the superiority of transectional gastrectomy over conventional distal gastrectomy. Future confirmation of the sentinel node concept through a multi-institutional validation study conducted by the Japanese Society of Sentinel Node Navigation Surgery would lead to widespread adoption of transectional gastrectomy.

A selective cyclooxygenase-2 inhibitor prevents inflammation-related squamous cell carcinogenesis of the forestomach via duodenogastric reflux in rats.

BACKGROUND: Duodenal reflux causes inflammation-related squamous cell carcinogenesis in the forestomach of rats without any carcinogens. The aim of this study was to investigate the efficacy of a selective cyclooxygenase (COX)-2 inhibitor, meloxicam, in preventing this carcinogenesis. METHODS: A series of 188 rats underwent a surgical duodenogastric reflux procedure and were divided into 2 groups. One group was given commercial chow (control group), and the other was given experimental chow containing meloxicam (0.3 mg/kg body weight/day) (meloxicam group). The animals were sequentially sacrificed at Weeks 20, 30, 40, 50, and 60 after surgery. The forestomach was examined for the presence of carcinoma, the incidence of reflux-related morphological changes, COX-2 expression, and its activity. RESULTS: At Week 60, squamous cell carcinoma developed in 8 of 21 animals (38%) in the control group, but none of 20 (0%) in the meloxicam group (P<.05). In addition, basal cell dysplasia developed in 19 of 21 (90%) animals in the control group, but only 4 of 20 (20%) in the meloxicam group (P<.01). COX-2 immunoreactivity was predominantly detected in macrophages in the epithelial stroma. Compared with nonsurgical rats, RNA expression of COX-2 in the epithelium was up-regulated, reaching peak at an early stage of Week 20 in both groups (P<.005). The expression of microsomal prostaglandin E synthase-1 was lower in the meloxicam group than in the control group. PGE2 production was significantly suppressed throughout the experiment in the meloxicam group compared with the control group (P<.005). CONCLUSIONS: Meloxicam was effective in preventing reflux-induced squamous cell carcinogenesis via an inflamed squamous epithelium.

A case of lymphocytic mastopathy requiring differential diagnosis from primary breast lymphoma.

Lymphocytic mastopathy is a benign breast disease characterized by dense fibrosis, lobular atrophy, and aggregates of lymphocytes in a periductal and perivascular distribution. The condition affects young to middle-aged women and frequently shows an association with diabetes mellitus or autoimmune disorders. Here, we report a case of the disease clinically and radiologically mimicking primary breast neoplasms. The patient was a 50-year-old woman without diabetes who presented with two firm lumps in her right breast. Breast imaging findings from mammography, ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI), respectively, revealed an abnormal appearance suspicious of malignancy. A core-needle biopsy specimen showed atypical accumulation of lymphoid cells, which was not easy to differentiate from primary breast lymphomas. Moreover, (18)fluorodeoxyglucose positron emission tomography (FDG-PET) examination detected abnormal uptake in the same lesions. Histological examination of a surgically obtained specimen showed characteristic appearance of lymphocytic mastopathy, which predominantly consisted of B-lymphocytes. In our case, it was difficult to distinguish this entity from breast cancer or low-grade B-cell lymphoma without surgical biopsy.

Chemoprevention of glandular stomach carcinogenesis through duodenogastric reflux in rats by a COX-2 inhibitor.

Duodenogastric reflux (DGR) causes glandular stomach carcinogenesis in rats without carcinogens. We aimed to investigate how this carcinogenesis might be prevented by a selective COX-2 inhibitor, meloxicam. A series of 188 Fisher 344 rats underwent a surgical DGR procedure and were divided into 2 groups. One group was given commercial chow (control group), and the other an experimental chow containing meloxicam [0.3 mg/kg bw/day] (meloxicam group). The animals were sequentially sacrificed at weeks 20, 30, 40, 50 and 60 after surgery. The stomachs were removed and examined for the presence of carcinoma, incidence of reflux-induced morphologic changes, COX-2 expression and its activity. Adenocarcinoma in the glandular stomach developed in 7 of 21 animals (33%) in the control group at week 60, but none of 20 (0%) in the meloxicam group (p < 0.01). Moreover, reflux-induced gastritis was definitely alleviated in the meloxicam group compared with the control group. COX-2 immunoreactivity was predominantly detected in stromal cells such as macrophages and fibroblasts. Compared with nonsurgical rats, RNA expression of COX-2 in the mucosa increased, reaching peak at an early phase of week 20 in both groups (p < 0.005). Expression of microsomal prostaglandin E synthase-1 was lower in the meloxicam group than in the control group. PGE(2) production was significantly suppressed throughout the experiment in the meloxicam group compared with the control group (p < 0.01). Gastric carcinogenesis via duodenal reflux was mediated by the COX-2 pathway in rats. Administration of meloxicam prevented this carcinogenesis by suppressing the inflammatory process.

[Subclassification of stage IV gastric cancer].

We studied the prognosis of 185 stage IV gastric cancer cases. The univariate analysis and multivariate analysis suggested that liver metastases (H) and peritoneal disseminations (P) were prognostic factors, the number of factors may be it, and lymph nodes metastases (N) and invasion to the other organs (T) were not it. Based on these findings, we proposed a subclassification of stage IV: IVa [T1-3N3-or T4N2] and IVb [the others]. The survival rates for IVa significantly exceeded those of IVb and did not differ from those of 25 stage IIIb gastric cancer cases.

[A case of adult neuroblastoma arising in the retroperitoneum following a poorly aggressive course].

A 69-year-old man complaining of enlarged cervical mass, appetite loss and lower abdominal pain was found to have abdominal tumors in heaps forming a large mass around the retroperitoneum. The biopsy specimen in the cervical mass showed undifferentiated carcinoma with neuroendocrine feature. This malignancy followed a poorly aggressive course and caused death in only 24 hospital days. The disease was diagnosed as undifferentiated neuroblastoma arising in the retroperitoneum by autopsy with appropriate immunohistochemical studies. Adult neuroblastoma in the peritoneum is rare and our case showed a aggressive behavior and unfortunate outcome.

Ingestion of thioproline suppresses rat esophageal adenocarcinogenesis caused by duodenogastroesophageal reflux.

Duodenogastroesophageal reflux causes esophageal adenocarcinoma in rats without the use of a carcinogen. This etiology is unclear, but may be associated with endogenous nitrosation in the gastrointestinal tract. Thioproline (TPRO) is an effective nitrite-trapping agent and blocks endogenous nitrosation. We investigated how ingested TPRO affected esophageal adenocarcinogenesis in rats with duodenogastroesophageal reflux (DGER) or gastroesophageal reflux (GER). A series of 200 male Fischer 344 rats received surgery to induce reflux of duodenogastric contents or gastric contents alone into the esophagus. The rats were separated into two divisions according to the surgical procedure employed (DGER or GER), and each division was further subdivided into two groups: one group was fed a special diet (CRF-1 containing 0.5% of TPRO); the other group was fed a standard diet (CRF-1). The rats were given no carcinogen and sacrificed at ten-week intervals from the 25th to the 45th week after surgery. Pathological examination was carried out using hematoxylin-eosin or immunohistochemical staining. Erosion, regenerative thickening, basal cell hyperplasia and columnar-lined epithelium (CLE) were found in both groups of the DGER rats. Adenocarcinoma (AC) appeared only in the DGER rats sacrificed at 35 and 45 weeks following surgery. The incidence of AC at the 45th week was significantly lower in the group of rats fed the diet containing TPRO, as compared to those fed the standard diet, whereas the incidences of CLE were the same for both groups. iNOS protein and nitrotyrosine protein were identified in the CLE and macrophages of the DGER group using immunohistochemical staining. There were no remarkable pathological changes in the esophagi of the rats which underwent the GER procedure. In conclustion, TPRO has an inhibitory effect on esophageal reflux-induced adenocarcinogenesis in rats in that it prevents the progression from CLE to AC.

A randomized phase III trial of postoperative adjuvant therapy with S-1 alone versus S-1 plus PSK for stage II/IIIA gastric cancer: Hokuriku-Kinki Immunochemo-Therapy Study Group-Gastric Cancer (HKIT-GC).

In this randomized multicenter Phase III study, patients with curatively resected Stage II/IIIA gastric cancer were assigned to postoperative adjuvant therapy with an oral fluoropyrimidine S-1 alone (2 weeks of treatment and 1 week of rest for 6 months, followed by 2 weeks of treatment and 2 weeks of rest for 6 months) or S-1 combined with an oral biological response modifier PSK (the same regimen of S-1 plus daily PSK for 12 months). The main objective was to evaluate the survival benefit and quality of life (QOL) of combined therapy. The primary end points were the time to relapse and the duration of survival after surgery, i.e. the rates of disease-free survival and overall survival at 3 and 5 years. The secondary end points were the relations of survival rates to drug compliance, QOL, adverse events, postoperative complications, relapse status, and the preoperative expression of immune or tumor markers. The sample size was 140 per treatment arm.

[A case of monolobar Caroli's disease].

The patient was a 45-year-old man, with no complaints. It was pointed out that he had a cystic lesion in the liver by abdominal ultrasonography at routine medical check-up. With close examinations, the tumor was multilocular cystic lesion in the right lobe of the liver, whose size was 35mm in diameter. We supposed it was a biliary cystadenoma (adenocarcinoma), echinococcosis, or degenerated hemangioma. And we performed partial hepatectomy. Finally, it was diagnosed as pure type monolobar Caroli's disease by pathological examination. This was a rare case of Caroli's disease which arose limitedly in monolobe. And we could curatively resect it by hepatectomy.

Duodenal juice stimulates oesophageal stem cells to induce Barrett's oesophagus and oesophageal adenocarcinoma in rats.

the present study was performed to examine the sequential process of the development of Barrett's oesophagus (BE) and oesophageal adenocarcinoma (ADC) induced by duodeno-oesophageal reflux (DER) in rats. Total gastrectomy was performed in male Wistar rats weighing approximately 250 g followed by reconstruction with oesophago-jejunostomy, which causes unavoidable DER without exposure to exogenous carcinogens. Animals were selected at random and sacrificed every 10 weeks after surgery until 50 weeks. Severe squamous oesophagitis with erosion, regenerative thickening (RT), and basal cell hyperplasia (BCH) were observed on the 10th week after surgery. On the 20th week, glandular structures that stained positively with Galactose oxidase-Schiff (foveolar metaplasia) were observed in the basal layer of the oesophageal squamous epithelium. On the 30th week, the glands developed and formed cysts that stained positively with concanavalin A (pyloric glandular metaplasia) and/or high-iron diamine and Alcian blue (intestinal metaplasia). From the 40th week after surgery, ADC cells surrounded by columnar-lined epithelium were found. Persistent stimulation with DER can alter the stem cells in the squamous epithelial basal layer leading to the formation of columnar-lined cells and subsequent ADC. Foveolar metaplasia was observed as part of the sequence of events leading to the development of columnar-lined epithelium (CLE), followed by the appearance of pyloric glandular metaplasia and intestinal metaplasia, completing the histogenesis of BE.

Evaluation of residual stomach motility after proximal gastrectomy for gastric cancer by electrogastrography.

The relationship between the motility and the size of the residual stomach after proximal gastrectomy was evaluated using electrogastrography (EGG). Based on fast Fourier transformation, recorded slow waves could be analyzed to obtain the following parameters: dominant frequency (DF), percentage normal frequency (% 3 cycles per minute [cpm]), and power ratio (PR). EGG parameters, the length of the greater curvature of the residual stomach (LGC), were recorded in 18 gastrectomized patients. Compared to 12 healthy controls, the gastrectomized patients had abdominal EGG parameters including lower %3cpm (43 +/- 21% vs 83 +/- 7%; P < 0.05), DF (2.2 +/- 0.4 vs 3.0 +/- 0.2 cpm; P < 0.05), and PR (1.5 +/- 0.8 vs 2.5+/- 0.8; P < 0.05). In relation to LGC and parameters, there was no difference between the patients whose LGC was > 20 cm and controls in PR (2.3+/- 0.9 vs 2.5+/- 0.8; n.s.). In conclusion, the motility of the residual stomach would be equal to that of the nonresected stomach as if the volume of the residual stomach was more than half.

Role of cyclooxygenase-2 in the carcinogenesis of gastrointestinal tract cancers: a review and report of personal experience.

Selective cyclooxygenase (COX)-2 inhibitors (coxibs) were developed as one of the anti-inflammatory drugs to avoid the various side effects of non-steroidal anti-inflammatory drugs (NSAIDs). However,coxibs also have an ability to inhibit tumor development of various kinds the same way that NSAIDs do. Many experimental studies using cell lines and animal models demonstrated an ability to prevent tumor proliferation of COX-2 inhibitors. After performing a randomized study for polyp chemoprevention study in patients with familial adenomatous polyposis (FAP),which showed that the treatment with celecoxib, one of the coxibs, significantly reduced the number of colorectal polyps in 2000, the U.S. Food and Drug Administration (FDA) immediately approved the clinical use of celecoxib for FAP patients. However, some coxibs were recently reported to increase the risk of serious cardiovascular events including heart attack and stroke. In this article we review a role of COX-2 in carcinogenesis of gastrointestinal tract, such as the esophagus, stomach and colorectum,and also analyze the prospect of coxibs for chemoprevention of gastrointestinal tract tumors.

Induction of gastric GIST in rat and establishment of GIST cell line.

Continuous administration of the direct-reacting carcinogen N-methyl-N'-nitro-N-nitrosoguanidine reportedly produces not only adenocarcinoma in rats, but also mesenchymal tumors. A large number of tumors diagnosed as gastrointestinal smooth muscle tumors actually represent gastrointestinal stromal tumors (GISTs) in human cases. We have induced mesenchymal tumors by duodenal reflux in rats. To clarify the differentiation of these mesenchymal tumors, immunohistochemical investigations were undertaken. In addition, the first culture model of GIST-DR derived from GIST induced by duodenal reflux was established. GIST-DR cells, both in vitro and in vivo, were strongly immunopositive for both KIT and CD34, and STI571 (Imatinib mesylate) blocked the proliferation of this cell line. The present results suggest that duodenal reflux plays a role in the histogenesis of GIST.